Composition and methods for inhibiting expression of hypoxia-inducible genes

Abstract

Methods are provided for interfering with a hypoxia-mediated transcriptional pathway using an agent that binds to a hypoxia response element and inhibits transcription of a hypoxia inducible gene associated therewith. Also provided are methods of treating a patient with a solid tumors, and compositions useful for treating a patient having solid tumors, including, for example, by administering an agent that binds to a hypoxia response element in a cell. Agents for the methods of the invention are provided including compositions comprising a pyrrole imidazole polyamide or a pharmaceutically acceptable salt or complex thereof.

Description

CLAIM OF PRIORITY [0001] This application claims benefit of priority to U.S. Provisional Application 60 / 577,901, filed Jun. 7, 2004 which is fully incorporated by reference herein, including all figures, tables, references and charts.GOVERNMENT SUPPORT [0002] This invention was made with government support under Grant No. GM57148 awarded by the National Institutes of Health. The United States government may have certain rights in this invention.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The invention relates generally to therapeutic compositions and methods and more specifically to methods of treating reducing or inhibiting translation of a hypoxia inducible gene by contacting cells with an agent that binds to an hypoxia response element associated with the gene. BACKGROUND INFORMATION [0005] Cancer remains a major cause of morbidity and mortality in humans. In addition to its impact on the cancer patient and family members, cancer inflicts a great burden on...

AI Technical Summary

Benefits of technology

[0011] The present invention is based upon the discovery of sequence specific DNA-binding polyamide agents which can regulate hypoxia-mediated transcriptional pathways. The DNA binding polyamide agents are designed to specifically bind to a hypoxia response element of hypoxia inducible genes. As a result of their unique binding properties, these agents reduce or inhibit expression of hypoxia inducible genes. This allows for a novel route to reducing or inhibiting angiogenesis.

[0014] In another aspect, the invention provides a method for interfering with a hypoxia-mediated transcriptional pathway in a cell. The method involves the step of contacting the cell with an agent which binds to a hypoxia response element. The binding of the agent and the hypoxia response element reduces or inhibits binding of a hypoxia inducible factor to the hypoxia response element, thereby reducing or inhibiting expression by a hypoxia inducible gene associated with the hypoxia response element.

[0015] In another aspect of the present invention, a method is provided for reducing the growth and / or metastatic spread of a tumor. The method involves contacting a tumor with an agent that binds to a DNA sequence encoding a hypoxia response element. By binding the hypoxia response element, the agent reduces or inhibits expression by a hypoxia inducible gene.

Problems solved by technology

Cancer remains a major cause of morbidity and mortality in humans.

In addition to its impact on the cancer patient and family members, cancer inflicts a great burden on society.

For example, the high cost of caring for and treating cancer patients contributes to increased cost of health insurance, which, in turn, results in a higher percent of uninsured people and, consequently, an increased economic burden on government social systems when the uninsured are sick or injured.

However, while surgery is useful for treating patients whose tumors are localized, or have only minimally spread, for example, to local lymph nodes, it has limited usefulness for patients with metastatic disease, or with systemic cancers such as leukemia or lymphoma.

However, chemotherapeutic treatments are generally not specific for tumor cells, instead, taking advantage of differences in proliferation rates of tumor cells as compared to corresponding normal cells.

As a result, chemotherapy generally is associated with severe side effects, and can be particularly devastating to rapidly renewing tissues such as blood forming tissues and epithelial tissues.

While specific agents have provided advances in cancer treatment by allowing treatment of systemic or metastatic disease without causing systemic harm to the patient, the specificity of the agents also means that they are limited to treating one or, at best, a very few different cancers.

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